Genetic loci associated with heart rate variability and their effects on cardiac disease risk

Ilja M. Nolte (), M. Loretto Munoz, Vinicius Tragante, Azmeraw T. Amare, Rick Jansen, Ahmad Vaez, Benedikt von der Heyde, Christy L. Avery, Joshua C. Bis, Bram Dierckx, Jenny van Dongen, Stephanie M. Gogarten, Philippe Goyette, Jussi Hernesniemi, Ville Huikari, Shih-Jen Hwang, Deepali Jaju, Kathleen F. Kerr, Alexander Kluttig, Bouwe P. Krijthe, Jitender Kumar, Sander W. van der Laan, Leo-Pekka Lyytikäinen, Adam X. Maihofer, Arpi Minassian, Peter J. van der Most, Martina Müller-Nurasyid, Michel Nivard, Erika Salvi, James D. Stewart, Julian F. Thayer, Niek Verweij, Andrew Wong, Delilah Zabaneh, Mohammad H. Zafarmand, Abdel Abdellaoui, Sulayma Albarwani, Christine Albert, Alvaro Alonso, Foram Ashar, Juha Auvinen, Tomas Axelsson, Dewleen G. Baker, Paul I. W. de Bakker, Matteo Barcella, Riad Bayoumi, Rob J. Bieringa, Dorret Boomsma, Gabrielle Boucher, Annie R. Britton, Ingrid Christophersen, Andrea Dietrich, George B. Ehret, Patrick T. Ellinor, Markku Eskola, Janine F. Felix, John S. Floras, Oscar H. Franco, Peter Friberg, Maaike G. J. Gademan, Mark A. Geyer, Vilmantas Giedraitis, Catharina A. Hartman, Daiane Hemerich, Albert Hofman, Jouke-Jan Hottenga, Heikki Huikuri, Nina Hutri-Kähönen, Xavier Jouven, Juhani Junttila, Markus Juonala, Antti M. Kiviniemi, Jan A. Kors, Meena Kumari, Tatiana Kuznetsova, Cathy C. Laurie, Joop D. Lefrandt, Yong Li, Yun Li, Duanping Liao, Marian C. Limacher, Henry J. Lin, Cecilia M. Lindgren, Steven A. Lubitz, Anubha Mahajan, Barbara McKnight, Henriette Meyer zu Schwabedissen, Yuri Milaneschi, Nina Mononen, Andrew P. Morris, Mike A. Nalls, Gerjan Navis, Melanie Neijts, Kjell Nikus, Kari E. North, Daniel T. O'Connor, Johan Ormel, Siegfried Perz, Annette Peters, Bruce M. Psaty, Olli T. Raitakari, Victoria B. Risbrough, Moritz F. Sinner, David Siscovick, Johannes H. Smit, Nicholas L. Smith, Elsayed Z. Soliman, Nona Sotoodehnia, Jan A. Staessen, Phyllis K. Stein, Adrienne M. Stilp, Katarzyna Stolarz-Skrzypek, Konstantin Strauch, Johan Sundström, Cees A. Swenne, Ann-Christine Syvänen, Jean-Claude Tardif, Kent D. Taylor, Alexander Teumer, Timothy A. Thornton, Lesley E. Tinker, André G. Uitterlinden, Jessica van Setten, Andreas Voss, Melanie Waldenberger, Kirk C. Wilhelmsen, Gonneke Willemsen, Quenna Wong, Zhu-Ming Zhang, Alan B. Zonderman, Daniele Cusi, Michele K. Evans, Halina K. Greiser, Pim van der Harst, Mohammad Hassan, Erik Ingelsson, Marjo-Riitta Järvelin, Stefan Kääb, Mika Kähönen, Mika Kivimaki, Charles Kooperberg, Diana Kuh, Terho Lehtimäki, Lars Lind, Caroline M. Nievergelt, Chris J. O'Donnell, Albertine J. Oldehinkel, Brenda Penninx, Alexander P. Reiner, Harriëtte Riese, Arie M. van Roon, John D. Rioux, Jerome I. Rotter, Tamar Sofer, Bruno H. Stricker, Henning Tiemeier, Tanja G. M. Vrijkotte, Folkert W. Asselbergs, Bianca J. J. M. Brundel, Susan R. Heckbert, Eric A. Whitsel, Marcel den Hoed, Harold Snieder () and Eco J. C. de Geus ()
Additional contact information
Ilja M. Nolte: University of Groningen, University Medical Center Groningen
M. Loretto Munoz: University of Groningen, University Medical Center Groningen
Vinicius Tragante: University Medical Center Utrecht
Azmeraw T. Amare: University of Groningen, University Medical Center Groningen
Rick Jansen: EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest
Ahmad Vaez: University of Groningen, University Medical Center Groningen
Benedikt von der Heyde: Molecular Epidemiology, Uppsala University
Christy L. Avery: Gillings School of Global Public Health, University of North Carolina
Joshua C. Bis: Cardiovascular Health Research Unit, University of Washington
Bram Dierckx: Department of Child and Adolescent Psychiatry/Psychology, Department of Child and Adolescent Psychiatry
Jenny van Dongen: Behavioral and Movement Sciences, VU University
Stephanie M. Gogarten: School of Public Health, University of Washington
Philippe Goyette: Montreal Heart Institute
Jussi Hernesniemi: Fimlab Laboratories
Ville Huikari: Center for Life Course Health Research, University of Oulu
Shih-Jen Hwang: Framingham Heart Study
Deepali Jaju: Sultan Qaboos University Hospital
Kathleen F. Kerr: School of Public Health, University of Washington
Alexander Kluttig: Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg
Bouwe P. Krijthe: Erasmus MC, University Medical Center Rotterdam
Jitender Kumar: Molecular Epidemiology, Uppsala University
Sander W. van der Laan: Laboratory of Experimental Cardiology, University Medical Center Utrecht
Leo-Pekka Lyytikäinen: Fimlab Laboratories
Adam X. Maihofer: University of California, San Diego
Arpi Minassian: University of California, San Diego
Peter J. van der Most: University of Groningen, University Medical Center Groningen
Martina Müller-Nurasyid: Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health
Michel Nivard: Behavioral and Movement Sciences, VU University
Erika Salvi: University of Milano
James D. Stewart: Gillings School of Global Public Health, University of North Carolina
Julian F. Thayer: The Ohio State University
Niek Verweij: University of Groningen, University Medical Center Groningen
Andrew Wong: MRC Unit for Lifelong Health and Ageing, University College London
Delilah Zabaneh: Institute of Psychiatry, Psychology & Neuroscience, King's College London
Mohammad H. Zafarmand: Academic Medical Center (AMC), University of Amsterdam
Abdel Abdellaoui: Behavioral and Movement Sciences, VU University
Sulayma Albarwani: College of Medicine and Health Sciences, Sultan Qaboos University
Christine Albert: Brigham and Women's Hospital, Harvard Medical School
Alvaro Alonso: Rollins School of Public Health, Emory University
Foram Ashar: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Juha Auvinen: Center for Life Course Health Research, University of Oulu
Tomas Axelsson: Molecular Medicine, Uppsala University
Dewleen G. Baker: University of California, San Diego
Paul I. W. de Bakker: Center for Molecular Medicine, University Medical Center Utrecht
Matteo Barcella: University of Milano
Riad Bayoumi: College of Medicine, Mohammed Bin Rashid University
Rob J. Bieringa: University of Groningen, University Medical Center Groningen
Dorret Boomsma: Behavioral and Movement Sciences, VU University
Gabrielle Boucher: Montreal Heart Institute
Annie R. Britton: University College London
Ingrid Christophersen: Cardiovascular Research Center, Massachusetts General Hospital
Andrea Dietrich: University of Groningen, University Medical Center Groningen
George B. Ehret: Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Patrick T. Ellinor: Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT
Markku Eskola: Heart Hospital, Tampere University Hospital
Janine F. Felix: Erasmus MC, University Medical Center Rotterdam
John S. Floras: University of Toronto
Oscar H. Franco: Erasmus MC, University Medical Center Rotterdam
Peter Friberg: Institute of Medicine, Sahlgrenska University Hospital, University of Gothenburg
Maaike G. J. Gademan: Academic Medical Center (AMC), University of Amsterdam
Mark A. Geyer: University of California, San Diego
Vilmantas Giedraitis: Molecular Geriatrics, Uppsala University
Catharina A. Hartman: Interdisciplinary Center Psychopathology and Emotion regulation, University of Groningen, University Medical Center Groningen
Daiane Hemerich: University Medical Center Utrecht
Albert Hofman: Erasmus MC, University Medical Center Rotterdam
Jouke-Jan Hottenga: Behavioral and Movement Sciences, VU University
Heikki Huikuri: Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu
Nina Hutri-Kähönen: Tampere University Hospital
Xavier Jouven: INSERM U970, Paris Descartes University
Juhani Junttila: Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu
Markus Juonala: University of Turku
Antti M. Kiviniemi: Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu
Jan A. Kors: Erasmus Medical Center
Meena Kumari: University College London
Tatiana Kuznetsova: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, University of Leuven
Cathy C. Laurie: School of Public Health, University of Washington
Joop D. Lefrandt: University of Groningen, University Medical Center Groningen
Yong Li: Institute for Medical Biometry and Statistics, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg
Yun Li: University of North Carolina
Duanping Liao: Penn State University College of Medicine
Marian C. Limacher: University of Florida College of Medicine
Henry J. Lin: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Cecilia M. Lindgren: Li Ka Shing Centre for Health Information and Discovery, The Big Data Institute, University of Oxford
Steven A. Lubitz: Program in Medical and Population Genetics, The Broad Institute of Harvard and MIT
Anubha Mahajan: Wellcome Trust Centre for Human Genetics, University of Oxford
Barbara McKnight: Cardiovascular Health Research Unit, University of Washington
Henriette Meyer zu Schwabedissen: Biopharmacy, University of Basel
Yuri Milaneschi: EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest
Nina Mononen: Fimlab Laboratories
Andrew P. Morris: Wellcome Trust Centre for Human Genetics, University of Oxford
Mike A. Nalls: Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health
Gerjan Navis: University of Groningen, University Medical Center Groningen
Melanie Neijts: Behavioral and Movement Sciences, VU University
Kjell Nikus: Heart Hospital, Tampere University Hospital
Kari E. North: Gillings School of Global Public Health, University of North Carolina
Daniel T. O'Connor: University of California, San Diego
Johan Ormel: Interdisciplinary Center Psychopathology and Emotion regulation, University of Groningen, University Medical Center Groningen
Siegfried Perz: Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health
Annette Peters: DZHK (German Centre for Cardiovascular Research), Partner site Munich Heart Alliance
Bruce M. Psaty: Cardiovascular Health Research Unit, University of Washington
Olli T. Raitakari: Turku University Hospital
Victoria B. Risbrough: University of California, San Diego
Moritz F. Sinner: University Hospital Munich, Ludwig-Maximilians-University
David Siscovick: The New York Academy of Medicine
Johannes H. Smit: EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest
Nicholas L. Smith: Group Health Research Institute, Group Health Cooperative
Elsayed Z. Soliman: Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine
Nona Sotoodehnia: Cardiovascular Health Research Unit, University of Washington
Jan A. Staessen: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, University of Leuven
Phyllis K. Stein: Heart Rate Variability Lab, Washington University School of Medicine
Adrienne M. Stilp: School of Public Health, University of Washington
Katarzyna Stolarz-Skrzypek: Interventional Electrocardiology and Hypertension, Jagiellonian University Medical College
Konstantin Strauch: Institute of Genetic Epidemiology, Helmholtz Zentrum München—German Research Center for Environmental Health
Johan Sundström: Cardiovascular Epidemiology, Uppsala University
Cees A. Swenne: Leiden University Medical Center
Ann-Christine Syvänen: Molecular Medicine, Uppsala University
Jean-Claude Tardif: Montreal Heart Institute
Kent D. Taylor: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Alexander Teumer: Institute for Community Medicine, University Medicine Greifswald
Timothy A. Thornton: School of Public Health, University of Washington
Lesley E. Tinker: Fred Hutchinson Cancer Research Center
André G. Uitterlinden: Erasmus MC, University Medical Center Rotterdam
Jessica van Setten: University Medical Center Utrecht
Andreas Voss: Institute of Innovative Health Technologies—IGHT Jena Ernst-Abbe-Hochschule Jena
Melanie Waldenberger: Institute of Epidemiology II, Helmholtz Zentrum München—German Research Center for Environmental Health
Kirk C. Wilhelmsen: Departments of Genetics and Neurology University of North Carolina
Gonneke Willemsen: Behavioral and Movement Sciences, VU University
Quenna Wong: School of Public Health, University of Washington
Zhu-Ming Zhang: Epidemiological Cardiology Research Center (EPICARE), Wake Forest School of Medicine
Alan B. Zonderman: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health
Daniele Cusi: Institute of Biomedical Technologies, CNR—Italian National Research Council
Michele K. Evans: Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health
Halina K. Greiser: German Cancer Research Centre
Pim van der Harst: University of Groningen, University Medical Center Groningen
Mohammad Hassan: College of Medicine and Health Sciences, Sultan Qaboos University
Erik Ingelsson: Molecular Epidemiology, Uppsala University
Marjo-Riitta Järvelin: Center for Life Course Health Research, University of Oulu
Stefan Kääb: University Hospital Munich, Ludwig-Maximilians-University
Mika Kähönen: Tampere University Hospital
Mika Kivimaki: University College London
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Diana Kuh: MRC Unit for Lifelong Health and Ageing, University College London
Terho Lehtimäki: Fimlab Laboratories
Lars Lind: Cardiovascular Epidemiology, Uppsala University
Caroline M. Nievergelt: University of California, San Diego
Chris J. O'Donnell: Framingham Heart Study
Albertine J. Oldehinkel: Interdisciplinary Center Psychopathology and Emotion regulation, University of Groningen, University Medical Center Groningen
Brenda Penninx: EMGO Institute for Health and Care Research and Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest
Alexander P. Reiner: Fred Hutchinson Cancer Research Center
Harriëtte Riese: Interdisciplinary Center Psychopathology and Emotion regulation, University of Groningen, University Medical Center Groningen
Arie M. van Roon: University of Groningen, University Medical Center Groningen
John D. Rioux: Montreal Heart Institute
Jerome I. Rotter: Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
Tamar Sofer: School of Public Health, University of Washington
Bruno H. Stricker: Erasmus MC, University Medical Center Rotterdam
Henning Tiemeier: Department of Child and Adolescent Psychiatry/Psychology, Department of Child and Adolescent Psychiatry
Tanja G. M. Vrijkotte: Academic Medical Center (AMC), University of Amsterdam
Folkert W. Asselbergs: University Medical Center Utrecht
Bianca J. J. M. Brundel: Institute for Cardiovascular Research, VU University Medical Center
Susan R. Heckbert: Cardiovascular Health Research Unit, University of Washington
Eric A. Whitsel: Gillings School of Global Public Health, University of North Carolina
Marcel den Hoed: Molecular Epidemiology, Uppsala University
Harold Snieder: University of Groningen, University Medical Center Groningen
Eco J. C. de Geus: Behavioral and Movement Sciences, VU University

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract Reduced cardiac vagal control reflected in low heart rate variability (HRV) is associated with greater risks for cardiac morbidity and mortality. In two-stage meta-analyses of genome-wide association studies for three HRV traits in up to 53,174 individuals of European ancestry, we detect 17 genome-wide significant SNPs in eight loci. HRV SNPs tag non-synonymous SNPs (in NDUFA11 and KIAA1755), expression quantitative trait loci (eQTLs) (influencing GNG11, RGS6 and NEO1), or are located in genes preferentially expressed in the sinoatrial node (GNG11, RGS6 and HCN4). Genetic risk scores account for 0.9 to 2.6% of the HRV variance. Significant genetic correlation is found for HRV with heart rate (−0.74

Date: 2017
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DOI: 10.1038/ncomms15805

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